Animals such as mammals and birds are often susceptible to parasite infestations. These parasites may be ectoparasites, such as fleas (Ctenocephalides felis, Ctenocephalides sp. and the like), ticks (including Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp. and the like), mites (Demodex sp., Sarcoptes sp., Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp., Linognathus sp., and the like), and flies (including Hematobia sp., Musca sp., Stomoxys sp., Dermatobia sp., Cochliomyia sp.), mosquitoes (family Culicidae) and the like. Animals may also be susceptible to infection by endoparasites such as filaria and worms.
Compounds that exhibit a high degree of activity against a wide range of ectoparasites including arthropods and insects are known in the art. One such class of compounds is the arylpyrazoles which are referred to, for example, in U.S. Pat. Nos. 5,122,530; 5,246,255; 5,576,429; 5,885,607; 6,010,710; 6,083,519; 6,096,329; 6,685,954; EP 0 234 119 and EP 0 295 117 (U.S. Pat. Nos. 5,232,940; 5,547,974; 5,608,077; 5,714,191; 5,916,618 and 6,372,774); EP 0 352 944 (U.S. Pat. No. 4,963,575); EP 0 780 378 (U.S. Pat. Nos. 5,817,688; 5,922,885; 5,994,386; 6,124,339; 6,180,798 and 6,395,906); EP 0 846 686 (U.S. Pat. No. 6,069,157); and WO 98/28278, all incorporated herein by reference.
The arylpyrazoles are known to possess excellent activity against ectoparasites, such as fleas and ticks. Within this family of compounds, fipronil, 5-Amino-3-cyano-I-(2,6-dichloro-4-trifluoro-methylphenyl)-4-trifluoromethylsulfinylpyrazole, has been found to be exceptionally potent against insects and acarids. Fipronil is the active ingredient in the well-known Frontline® family of products for treatment and control of fleas, ticks and chewing lice in cats and dogs. Fipronil binds to the gamma aminobutyric acid (GABA) receptors in the cell membranes of invertebrate neurons, functionally stabilizing the closed form of the channel resulting in death. Fipronil has the following chemical structure:

Fipronil has been commercialized for several years with use in both the agricultural sector and for the protection of animals against ectoparasites. Accordingly, efficient processes to prepare fipronil on a large scale are known.
Recently, 1-aryl-5-alkyl pyrazole derivatives that exhibit exceptional activity against ectoparasites, including fleas and ticks, were reported in WO 2008/005489 and US 2008/0031902 (now U.S. Pat. No. 7,759,381 B2) to Lee et al., incorporated herein by reference. The 1-aryl-5-alkyl pyrazole compounds differ from fipronil, inter alia, in that they are substituted at the 5-position of the pyrazole ring with an alkyl or haloalkyl group rather than an amino group. In addition, certain 1-aryl-5-alkylpyrazole compounds described in the publications include mixed halogen substitution on the phenyl ring and on the 4-sulfinyl group. The known processes for the preparation of fipronil are not appropriate for the synthesis of the new 1-aryl-5-alkylpyrazole compounds.
WO 02/058690 and US 2004/0087627 refer to the synthesis of pyrazoles bearing a (2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl))ethyl substituent by reaction of a 1,3-diketone and phenylhydrazine bearing the 1-hydroxy-1-(trifluoromethyl)ethyl substituent (Scheme 4, page 11, US 2004/0087627). The synthesis of a specific compound by this method, 5-methyl-1-[(1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester is mentioned (US 2004/0087627, pages 23-24, Example 8). However, there appeared to be no examples where a 3,4,5-disubstituted pyrazole is prepared except in the presence of a 5-amino group or when all three substitutions are the same (methyl).
Synthesis of 3-ester-4-unsubstituted pyrazoles is also referred to in US 2005/0020564 (page 10, Scheme 3).
WO 2008/005489 and US 2008/0031902 A1 describe the synthesis of 1-aryl-5-alkylpyrazole compounds by a process wherein 2-thio-1,3-diketone derivatives are made by reacting a sulfenyl halide reagent with 1,3-diketone compounds, which are further reacted with a suitably substituted arylhydrazine compound to produce a 1-aryl-5-alkylpyrazole compound, which may be further elaborated to produce the desired pyrazole compounds. However, the process described utilizes haloalkyl sulfenyl halide reagents (e.g. trifluoromethyl sulfenyl chloride and dichlorofluoromethyl sulfenyl chloride), which are particularly hazardous and difficult to source. Accordingly, there is a need for improved processes for the preparation of 1-aryl pyrazole compounds which contain a carbon-linked group at the 5-position of the pyrazole ring, including 1-aryl-5-alkylpyrazole compounds, that are cost effective and adaptable to scale up.
Any and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. The citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.